ALS is a multistep process in South Korean, Japanese, and Australian patients

Abstract

ObjectiveTo establish whether amyotrophic lateral sclerosis (ALS) is a multistep process in South Korean and Japanese populations when compared to Australian cohorts.MethodsWe generated incident data by age and sex for Japanese (collected between April 2009 and March 2010) and South Korean patients with ALS (collected between January 2011 and December 2015). Mortality rates were provided for Australian patients with ALS (collected between 2007 and 2016). We regressed the log of age-specific incidence against the log of age with least squares regression for each ALS population.ResultsWe identified 11,834 cases of ALS from the 3 populations, including 6,524 Australian, 2,264 Japanese, and 3,049 South Korean ALS cases. We established a linear relation between the log incidence and log age in the 3 populations: Australia r2 = 0.99, Japan r2 = 0.99, South Korea r2 = 0.99. The estimate slopes were similar across the 3 populations, being 5.4 (95% confidence interval [CI], 4.8–5.5) in Japanese, 5.4 (95% CI, 5.2–5.7) in Australian, and 4.4 (95% CI, 4.2–4.8) in South Korean patients.ConclusionsThe linear relationship between log age and log incidence is consistent with a multistage model of disease, with slope estimated suggesting that 6 steps were required in Japanese and Australian patients with ALS while 5 steps were needed in South Korean patients. Identification of these steps could identify novel therapeutic strategies.

Cardiovascular disease, psychiatric diagnosis and sex differences in the multistep hypothesis of amyotrophic lateral sclerosis

“…Using population‐based registry data from Denmark, the regression coefficient of log‐incidence on log‐age is b = 4.6, which is relatively consistent with the previously published Western European [2,5], Australian [3] and Southeast Asian [4] data. These results are interpreted [1,2] to imply that ALS is the result of five to six ( i.e.…”

“…When data were analysed together in 5‐year age groups, the results were interpreted to suggest that a sequence of four to six distinct steps preceded the onset of disease (regression coefficient [b] +1). More recently, this has been replicated in datasets outside of Europe in Australian [3], South Korean and Japanese [4] cohorts and has also been extended to include genetic screening results from Italian and Irish registries [5]. Rare genetic mutations are already well‐known to be significant contributors to ALS for ~5% of cases [6,7], and the relationship between incidence and age of onset suggested fewer steps to disease are required for mutation carriers despite small sample sizes in the analyses, with a range of 15 to 74 carriers per gene.…”

“…Comparison of the coefficient of the line between groups was tested in R [17] using a two‐tailed Wald test with results plotted using the ggplot2 package. To analyse differences between males and females, our results were meta‐analysed using weighted inverse variance with reported coefficients (Table S1) [2–4].…”

“…In this study, we test the multistep hypothesis in ALS data and investigate whether those with ALS and a prior psychiatric or CVD diagnosis provide evidence consistent with fewer steps to disease. We also examine whether differences in sex alter the steps to disease, as this has been inconsistently reported [3,4]. We use the Danish population‐based registry data national records.…”

High-Throughput Genetic Testing in ALS: The Challenging Path of Variant Classification Considering the ACMG Guidelines

“…A unifying theory that considers both the contribution of genetic variants and their interplay with the “environment” has been proposed in the so-called “multi-step model”. It suggests that the pathological process underlying the disease could exist from birth, but the accumulation of variants, toxic effects of proteins, and environmental factors are needed to trigger the disease [ 169 , 170 , 171 ]. Variants in some genes, such as SOD1 and C9orf72 , could have a more severe effect, while multiple variants in other genes with a lower impact are needed to exceed the threshold [ 172 , 173 , 174 , 175 , 176 ].…”